What are the treatment alternatives for hyperlipidemia in patients intolerant to statins (HMG-CoA reductase inhibitors)?

From the Guidelines

For patients intolerant to statins, the most effective treatment alternative for hyperlipidemia management is ezetimibe, followed by PCSK9 inhibitors, inclisiran, and bempedoic acid, as these options have been demonstrated to be safe and well-tolerated, and improve lipid parameters in statin-intolerant patients 1. When considering treatment alternatives, it is essential to evaluate the patient's specific lipid abnormality, cardiovascular risk, comorbidities, and the nature of statin intolerance.

• Ezetimibe (10 mg daily) is often the first alternative, working by reducing intestinal cholesterol absorption rather than inhibiting cholesterol synthesis.
• PCSK9 inhibitors like evolocumab and alirocumab are highly effective, reducing LDL cholesterol by 50-70%, but their use is recommended for high-risk patients with primary hypercholesterolaemia and mixed dyslipidaemia who are intolerant to statins or who fail to meet target LDL cholesterol levels 1.
• Bempedoic acid (180 mg daily) is a newer option that works similarly to statins but acts in the liver rather than muscles, potentially causing fewer muscle-related side effects, and has been shown to reduce LDL-C levels by 15% to 25% with low rates of muscle-related adverse effects 1.
• Inclisiran, a siRNA targeting PCSK9, is also a viable option for patients with statin intolerance, although its efficacy and safety profile are still being evaluated.
• Combination therapy, such as combining bempedoic acid with ezetimibe, may be necessary to achieve lipid goals, and has been shown to lower LDL-C levels by approximately 35% 1. It is crucial to individualize treatment selection and monitor patients closely to minimize adverse effects and maximize the benefits of treatment, as recommended by the European guidelines on cardiovascular disease prevention in clinical practice 1.

From the FDA Drug Label

The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −71% (95% CI: −74%, −67%; p < 0.0001) and −63% (95% CI: −68%, −57%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. The Cholesterol-Lowering Atherosclerosis Study (CLAS) was a randomized, placebo-controlled, angiographic trial testing combined colestipol and niacin therapy in 162 non-smoking males with previous coronary bypass surgery.

Treatment alternatives for hyperlipidemia in patients intolerant to statins include:

• Evolocumab (REPATHA): a monoclonal antibody that significantly reduces LDL-C levels and the risk of cardiovascular events.
• Niacin (nicotinic acid): a lipid-lowering agent that has been shown to reduce the risk of nonfatal, recurrent myocardial infarction and disease progression in patients with hyperlipidemia.

These alternatives may be considered for patients who are intolerant to statins, but the choice of treatment should be individualized based on the patient's specific needs and medical history 2 3.

From the Research

Hyperlipidemia Treatment Alternatives for Statin Intolerance

• Statin intolerance is a common issue in patients with hypercholesterolemia, leading to undertreatment and increased risk of cardiovascular disease 4, 5, 6, 7.
• Several non-statin therapies are available for statin-intolerant patients, including ezetimibe, PCSK9 monoclonal antibodies, bile acid sequestrants, and proprotein convertase subtilisin-kexin type 9 inhibitors 5, 6, 7, 8.
• Alternative treatment approaches for statin-intolerant patients include:
  • Lowering the dose of statin or using intermittent dosages 5, 6.
  • Combining a statin with other lipid-lowering drugs, such as ezetimibe or PCSK9 inhibitors 5, 6, 7.
  • Using non-statin regimens, such as ezetimibe, bile acid sequestrants, or proprotein convertase subtilisin-kexin type 9 inhibitors, alone or in combination 5, 6, 7, 8.
  • Considering new hypolipidemic therapies, such as gene editing, which may become available in the future 6.
• The choice of treatment alternative depends on the individual patient's needs and circumstances, and a personalized approach to cholesterol reduction is recommended 4, 6, 7.

Non-Statin Therapies

• Ezetimibe is a commonly used non-statin therapy for statin-intolerant patients, which can be used alone or in combination with a statin or other lipid-lowering drugs 5, 6, 7, 8.
• PCSK9 monoclonal antibodies are another option for statin-intolerant patients, which can be used to achieve significant reductions in LDL cholesterol levels 4, 5, 6, 7.
• Bile acid sequestrants and proprotein convertase subtilisin-kexin type 9 inhibitors are also available as non-statin therapies for statin-intolerant patients 5, 6, 7, 8.

Treatment Goals

• The primary goal of treatment for statin-intolerant patients is to reduce LDL cholesterol levels and achieve optimal cardiovascular risk reduction 4, 5, 6, 7.
• Any reduction in LDL cholesterol levels can provide some benefit in reducing cardiovascular risk, regardless of the lipid-lowering drugs used 7.